One method of obtaining pharmaceutical products involves the use of an inert spherical bead which is coated with a drug in powder form. This technique, referred to in the art as "powder layering", generally involves the surface of the beads being coated with a binder solution, with the drug being applied onto the beads in powder form. This technique is usually suitable for the preparation of a wide range of drugs in immediate release form.
Powder layering techniques are well-known in the art, and are generally considered to work best with drugs which are freely soluble in water. Such drugs may be powder-layered directly onto the surface of tacky inert beads alone, or with additional excipients. In certain instances, it is preferable to use a spheronizing agent to add in the processing (layering) of the drug onto the beads. This is the case when the drug to be powder-layered is not freely water soluble.
U.S. Pat. No. 2,738,303 describes a sympathomimetic preparation which consists of small pellets coated with various thicknesses of a material slowly digestible or dispersible in the gastrointestinal tract. These pellets are prepared by placing small sugar pellets (non-pareil seeds) from 12-40 mesh in a rotating coating pan, wetting the sugar pellets using syrup U.S.P. or gelatin, and then coating them with a powder of the sympathomimetic. Thereafter, the powder-coated pellets are said to be extended by coating with a wax-fat coating such as a mixture of glyceryl monostearate and beeswax. In each of the examples, the non-pareil seeds were powder-layered to a low load (e.g., less than 50% of the total weight of the powder-layered pellet).
U.S. Pat. No. 5,026,560, which describes a method for producing powder-layered granules which are said to be spherical and which are said to be suitable for the application of a further coating for controlled release. Therein, granules are prepared by coating seed cores with a spraying powder contained a drug and a low substituted hydroxypropylcellulose powder, while at the same time spraying the seed cores with an aqueous binder. The powder contains 5-90 percent by weight of the low substituted hydroxypropylcellulose (preferably 10-60) and 2-70 percent by weight of drug (preferably 5-50 percent). The ratio of the aqueous binder to powder is said to be 1:1-1:2. The granules thereby produced are said to be spherical and to have an excellent hardness and disintegration.
WO 93/07861 describes multiphase microspheres containing a molecular compound dispersed in polymeric matrix which are said to achieve drug loading efficiencies between 80 and 100 percent. Particular ratios of water/oil emulsion to polymer and concentration of surfactant and dispersion media such as mineral oil is used to provide the beneficial result.
The use of organic solvents in the preparation of pharmaceutical formulations is considered undesirable because of inherent problems with regard to flammability, carcinogenicity, environmental concerns, cost, and safety in general. Therefore, it would be desirable to manufacture an immediate release morphine sulfate product or other therapeutically effective agent-containing product without the use of such organic solvents.
Many of the oral opioid analgesic formulations that are currently available in the market must be administered every four to six hours daily with a selected few formulated for less frequent 12 hour dosing. There is a need in the art to develop drug formulations which provide a duration of effect lasting longer than twelve hours such as a drug that may be administered to a patient only once a day.
Morphine, which is considered to be the prototypic opioid analgesic, has been formulated into 12 hour controlled-release formulations (i.e., MS Contin.RTM. tablets, commercially available from Purdue Frederick Company).
An orally administrable morphine formulation which would provide an extended duration of effect would be highly desirable. Such an oral sustained-release formulation of an opioid analgesic would provide effective steady-state blood levels (e.g., plasma levels) of the drug when orally administered such that a duration of effect greater than 12 hours, and more preferably, of about 24 hours or more, which formulation is fully bioavailable as well.
It would also be highly desirable to provide similar orally-administrable formulations containing therapeutically effective agents other than morphine.